This highly collaborative multi-disciplinary initiative will test the feasibility and impact on physicians and parents of genomic sequencing in the newborn period to assess future risk of childhood onset disease, as well as to guide diagnosis and treatment of sick newborns. A pipeline and process will be developed for reporting results of genomic sequencing to neonatologists and pediatricians, and a pilot clinical trial will be conducted to explore the impact of delivering genomic sequencing results in the newborn period. To evaluate the use of genomic screening in healthy newborns, 240 newborn infants and their parents will be enrolled shortly after birth at Brigham and Women's Hospital. To evaluate the use of early genomic screening as a resource for clinicians caring for infants who are ill, 240 newborns from the NICU at Boston Children's Hospital will be enrolled along with their parents. The trial will randomize these 480 newborns to receive either 1) clinically meaningful information derived from genomic sequencing and current newborn screening or 2) only current newborn screening as standard of care. Project 1 will rapidly sequence, analyze arid interpret genomic sequencing in a CLIA-approved pipeline and deliver an understandable and useful report to the family and pediatric care team of newborns in both groups. Project 2 will enroll newborns and their parents into the protocol, provide a team of genetics experts as a resource for families and pediatricians, and safely monitor the use of genomic information in clinical practice. Project 3 will examine preferences and motivations of enrolled parents, evaluate the flow and utilization of genomic information within clinical interactions and assess understanding, behavior, medical consequences and healthcare costs associated with the use of genomic sequencing in newborns. RELEVANCE: This initiative will significantly accelerate the use of genomics in clinical pediatric medicine by creating and safely testing novel methods for integrating sequencing into the care of newborns. It will test a new paradigm for newborn screening, in which genomic data is available as a resource throughout infancy and childhood to inform clinical care.